(1) Field of the Invention
The present invention relates to new compounds used as medicines for improving symptoms caused by thromboxane and the process therefor. In more detail, this invention relates to novel pinane type sulfonamide derivatives to which unsaturated fatty acid is attached and the process therefor. The compounds of the present invention are used as antithrombotic, anti-vasoconstricting, and anti-bronchoconstricting drugs.
(2) Prior Art
The general course of atherosclerosis, which is regarded as the main risk factor of myocardial infarction and cerebral infarction, begins in the arterial intima with mucoid accumulation and fibroblast formation, progressively followed by degeneration, deposition of lipid and cholesterol and destruction and atheromasia of the intima tissue, with gradual formation of high-degree and localized hypertrophy in the intima. The atherosclerosis has long been regarded to be caused by thrombuse formation and fibrin deposition, but recent discoveries of thromboxane A.sub.2 (TXA.sub.2) by Samuelsson et al. and prostacycline (PGI.sub.2) by Vane et al. have revealed an interaction between platelets and vessel wall. Platelets are said to play an important role in the onset and progress of atherosclerosis. Therefore, it is now recognized that the use of antithrombotic drugs, particularly drugs which inhibits platelet aggregration, are effective for the treatment of atherosclerotic diseases.
In addition to the conventional antithrombotic drugs such as heparin and coumarin compounds, certain types of prostaglandins are known to have a potent platelet aggregation inhibitory action. From these facts, prostaglandin derivatives have attracted much attention as possible antithrombotic drugs. For example, analogues of prostaglandin E.sub.1 and I.sub.2 receptor agonists have been developed. Since thromboxane A.sub.2 shows potent platelet aggregation and vasoconstriction action, thromboxane A.sub.2 synthesis inhibitors, such as cyclooxygenase inhibitors and thromboxane synthetase inhibitors, and thromboxane A.sub.2 receptor antagonists, have been developed. The thromboxane A.sub.2 receptor antagonists include 13-APA (Venton D. L. et al., J. Med. Chem., 22, 824 (1979)), PTA.sub.2 (Lefer A. M. et al., Proc. Natl. Acad. Sci. U.S.A., 76, 2566, (1979)), BM-13177 (Lefer A. M. et al., Drugs of Today, 21, 283 (1985)), SQ-29548 (Ogletree et al., J. Pharmacol. Exp. Ther., 34, 435, (1985)) or the like. The thromboxane A.sub.2 receptor antagonists are also disclosed in Japan Kokai No. 83-13551, Japan Kokai No. 86-49, USP 4,654,357 or the like.
When thrombin acts on platelets, cyclooxygenase is activated. By activation of cyclooxygenase, thromboxane A.sub.2 is produced enzymatically in platelets, vessel wall, and various other cells, from arachidonic acid through prostaglandins G.sub.2 and H.sub.2. This product has various potent physiologic or pathogenic actions. In particular, the potent platelet aggregation action and the action constricting the smooth muscle of bronchi, and of coronary, cerebral and pulmonary arteries, etc. are considered to be the factors which relate to the onset and progress of such circulatory and respiratory diseases as angina pectoris, myocardial infarction, cerebral infarction, and bronchial asthma. Moreover, it is said that the strong action occures even at a concentration of 10.sup.-10 to 10.sup.-11 M. Therefore, increasing attention has been paid to the development of thromboxane A.sub.2 antagonists or inhibitors as anti-thrombotics, anti-vasoconstrictives or anti-bronchoconstrictives. Inhibitors, however, have some problems in view of that they influence on prostaglandins which bear various important roles other than thromboxane A.sub.2 and uncontrollable thromboxane-like harmful effects are caused by accumulated substrates such as prostaglandins H.sub.2. So, development of antagonists has especially been sought.